Table 2.

Autophagy is a predominant mechanism that affects pre- and post-fertilization processes.

	Stages	Findings	Refs
Pre-fertilization	Ovarian pool establishment	Autophagy acts in the formation and assembly of primordial follicles and is crucial for nutrient supply. Non-suckling starvation during the early neonatal stage promotes primordial follicle formation through autophagy activation and apoptosis suppression. The augmentation of autophagy, and increase in BECN1 and MAP1LC3, cause a delay in germ cell cyst breakdown but the inhibition of apoptosis and promotion of the oocytes’ survival. Lysosome amplification in oocytes upon birth, cytoplasmic acidification of germ cells, and the levels of MAP1LC3B and BECN1 that autophagy is the main mechanism responsible for the germ cell loss in the perinatal ovary, thereby inhibiting autophagy preserve the ovarian germ cell pool. Mcl-1, for example, reduces autophagic-dependent cell death.	[97,101,103,108,112,114]
	GC differentiation	Autophagic members, ATG5 and BECN1, are required for GC differentiation mediated through WT1 degradation. Inhibition of CTSB cause GC survival by reducing autophagy, and apoptosis, increasing E2 and P4, and elevating GC proliferation.	[109,111]
	Follicular atresia	The efficient regression and elimination of atretic follicles and appropriate ovarian remodeling need autophagy, apoptosis, and the crosstalk between these two processes along with mitochondrial remodeling. TNF reduces the number of released oocytes and promotes unruptured follicle cell death through apoptosis and autophagy for tissue repair and remodeling of the ovaries.	[116,117,121,122]
	Oocytes and Oogenesis	The highest relative expression levels of BECN1 can be found in the primordial oocytes. BECN1 expression is found throughout the follicle but not in the ovarian cortex or medulla. ATG7 expresses at all oocyte stages from primordial to antral without any significant differences. Mitophagy, regulated by RAB7, controls oocyte meiosis and determines oocyte quality. Autophagy contributes to cyst breakdown and primordial folliculogenesis by regulating the expressions of oocyte growth factors as well as eliminating ROS. Autophagy- and apoptosis-dependent cell death are inhibited during oogenesis. During the late developmental stages of oogenesis, autophagy, not apoptosis, is responsible for the programmed cell death of follicular epithelium.	[99,102,106,107,113,123,124]
	Luteolysis	The autophagic role during the luteolysis process is initiated through luteolytic signaling via PGF2A- Ca2+-AMPK. The luteinization of GCs during early corpus luteum formation is regulated by HIF1A – BNIP3 mediated through autophagy, but not apoptosis. Autophagy regulates the life span of the corpus luteum, involving in a promoting cell survival pattern rather than in cell death.	[125–127]
Fertilization	Fertilization	The inactivity of Mapk1-Mapk3 in unfertilized eggs leads to apoptosis-dependent death and autophagy acts against it as a survival program. The induction of autophagy in embryos upon fertilization is independent of MTORC1, but it is related to PI3K. Although autophagy is induced after fertilization, it is not essential for oogenesis or fertilization. However, post-fertilization autophagy is essential for development. It seems that autophagy is essential for protein synthesis after the 2-cell stage.	[128,129]
	Elimination of paternal organelles	As mentioned above, autophagy is not important for fertilization, but it is induced by fertilization which is essential for the paternal mitochondria elimination. Immediately after fertilization, the paternal mitochondria are degraded by vesicles originating in the egg through endocytic and autophagic pathways. Paternal mitochondria are eliminated gradually involving lysosomal, autophagic, and ubiquitination pathways.	[80,130–134]
	Elimination of maternal organelles	Autophagy is triggered by fertilization and is responsible for the degradation of unnecessary maternal proteins in oocytes as well as the synthesis of new proteins encoded by the zygotic genome. Moreover, the regulated maternal transmission of mitochondria relies on mitophagy.	[134,135]
Embryonic development	Embryogenesis	The augmentation of autophagy improves the pre-implantation development of embryos. The artificial activation of autophagy leads to greatly improved development of embryos, rarely arrestment during 2- to 4-cell and 4-cell to morula stage transition, and development to the blastocyst stage with high efficiency. Activation of autophagy by MIR291A and MIR291B suppression leads to the promotion of the first cleavage and blastocyst formation in embryos. In fact, autophagy determines embryo viability and quality. In other words, autophagy is necessary for the completion of normal embryogenesis, and the survival of the embryo.	[136–140]
	Implantation	Autophagic flux and lysosomal activity are involved in the proceeding of stages related to implantation. The lysosomes are involved in the transfer and digestion of materials from the zona pellucida within the blastocyst. The activity and localization of lysosomes in the uterus EC alter toward autophagy after mating. Moreover, autophagic vacuoles are involved in the autolysis of the host cells. After implantation, the changes in lysosomes and autophagic activity allow the trophoblast to invade the deeper areas of the uterine wall.	[141,142]

Note: Autophagic flux in cooperation with various signaling pathways as well as apoptosis can be considered the main regulator of the pre- and post-fertilization processes. Although most studies indicate the essential role of autophagy in germ cell survival, some have suggested that inhibition of autophagy at certain stages is involved in maintaining the ovarian reserve. Successful fertilization and embryonic development require precise regulation of autophagy.